Disclosed is the title compound which has been found to be significantly more water soluble than other acid addition salts of the morphinane nucleus.
|
1. 17-cyclobutylmethyl-3-hydroxy-8β-methyl-6-methylene-morphinane methanesulfonate.
|
|||||||||||||||||||||||||||||||
Morphine is a well known narcotic analgesic having the structural formula: ##STR1## Morphine and its structurally related relatives are extremely effective for the relief of moderate to severe pain, however, these compounds are narcotic and most possess dependence-inducing liability and other side effects such as emesis, constipation, sweating, respiratory depression and myosis which make them less than ideal analgesics. A compound with the appropriate profile of analgesic (agonist) and narcotic antagonist activity has potential for treatment of moderate to severe pain without the liability of drug dependence or drug abuse. A compound having the desired profile, 17-cyclobutylmethyl-3-hydroxy-8β-methyl-6-methylene-morphinane, is disclosed in copending application Ser. No. 138,102, filed Apr. 21, 1980. This compound is well suited for use as a strong analgesic because of its agonist/antagonist profile.
Compounds of the type under consideration herein can be administered in the form of their free base, however, in many cases they are converted to their acid addition salts to increase their water solubility. Increased water solubility is desirable because it aids in the formulation of aqueous solutions for parenteral administration and assures a more rapid and uniform absorption or oral administration.
While the conversion of compounds of this type to their acid addition salts is known to have an effect on solubility, it cannot be predicted what effect a particular acid will have on the solubility of any specific compound.
The present invention is 17-cyclobutylmethyl-3-hydroxy-8β-methyl-6-methylene-morphinane methanesulfonate.
The method practicing the invention is illustrated by the following example:
Preparation and determination of the solubility of various acid addition salts of 17-cyclobutylmethyl-3-hydroxy-8β-methyl-6-methylene-morphinan was accomplished as follows:
To a stirred solution of the free base of the title compound, (1.01 g., 3 mmole), in absolute ether (60 ml.) was added methanesulfonic acid (0.214 ml., 317 mg., 3.3 mmole). The mixture was stirred at room temperature for 30 minutes and then the white crystals were collected, washed with ether and dried to give 915 mg. (70%) of the salt, m.p. 172°-188° C. Recrystallization of this material from boiling acetone (∼100 ml.) gave 514 mg. (40%) of pure salt, m.p. 245°-250°C Alternatively, the salt may be recrystallized from methanol-ethyl acetate.
Anal. Calcd. for C23 H31 NO.CH3 SO3 H: C, 66.48; H, 8.14; N, 3.23. Found: C, 66.81; H, 8.37; N, 2.96.
The hydrochloride salt, m.p. 218°-220°C, was prepared in a similar fashion and obtained in pure form by recrystallization from methanol-ethyl acetate.
Anal. Calcd. for C23 H31 NO.HCl: C, 73.87; H, 8.62; N, 3.75. Found: C, 73.73; H, 8.53; N, 3.73.
The hydrobromide salt, m.p. 210°-217°C, was obtained in crystalline form from ether.
Anal. Calcd. for C23 H31 NO.HBr: C, 66.02; H, 7.71; N, 3.35. Found: C, 65.90; H, 7.57; N, 3.19.
Attempts to prepare the fumarate, tartrate, maleate, citrate, phosphate, acetate and sulfate salts were unsuccessful because these salts could not be obtained in analytically pure form. This was the case because they formed noncrystalline gels or mixtures of mon- and di-basic salts which could not be readily purified.
Solubility determinations were carried out by the addition of known portions of distilled water to a weighed sample of the salt until solution occurred with brief warming in a 50°C water bath followed by shaking. Unexpectedly, the methanesulfonate salt was found to be soluble to the extent of 4% in distilled water. The analytically pure hydrochloride and hydrobromide salts were soluble to the extent of about 0.5%.
Kotick, Michael P., Polazzi, Joseph O.
| Patent | Priority | Assignee | Title |
| 5250695, | Jun 15 1992 | Miles Inc. | Use of specific counteranions to modify the solubility of tetrazolium salts |
| 6387917, | Oct 20 1999 | Archimedes Development Limited | Salts of opioid analgesics, particularly morphine, and methods of using same |
| Patent | Priority | Assignee | Title |
| 1892019, | |||
| 4259329, | Oct 17 1979 | Miles Laboratories, Inc. | 17-Cyclobutylmethyl-3-hydroxy-β-methyl-6-methylene morphinane, and methods of treating pain with them |
| Executed on | Assignor | Assignee | Conveyance | Frame | Reel | Doc |
| Feb 02 1981 | Miles Laboratories, Inc. | (assignment on the face of the patent) | / | |||
| Aug 28 1981 | KOTICK, MICHAEL P | MILES LABORATORIES, INC , A CORP OF DE | ASSIGNMENT OF ASSIGNORS INTEREST | 003974 | /0395 | |
| Aug 28 1981 | POLAZZI, JOSEPH O | MILES LABORATORIES, INC , A CORP OF DE | ASSIGNMENT OF ASSIGNORS INTEREST | 003974 | /0395 |
| Date | Maintenance Fee Events |
| Aug 05 1985 | M170: Payment of Maintenance Fee, 4th Year, PL 96-517. |
| Nov 13 1989 | M171: Payment of Maintenance Fee, 8th Year, PL 96-517. |
| Dec 20 1993 | M185: Payment of Maintenance Fee, 12th Year, Large Entity. |
| Dec 20 1993 | M186: Surcharge for Late Payment, Large Entity. |
| Date | Maintenance Schedule |
| Jun 08 1985 | 4 years fee payment window open |
| Dec 08 1985 | 6 months grace period start (w surcharge) |
| Jun 08 1986 | patent expiry (for year 4) |
| Jun 08 1988 | 2 years to revive unintentionally abandoned end. (for year 4) |
| Jun 08 1989 | 8 years fee payment window open |
| Dec 08 1989 | 6 months grace period start (w surcharge) |
| Jun 08 1990 | patent expiry (for year 8) |
| Jun 08 1992 | 2 years to revive unintentionally abandoned end. (for year 8) |
| Jun 08 1993 | 12 years fee payment window open |
| Dec 08 1993 | 6 months grace period start (w surcharge) |
| Jun 08 1994 | patent expiry (for year 12) |
| Jun 08 1996 | 2 years to revive unintentionally abandoned end. (for year 12) |